Abstract
Peri-procedural management of oral anticoagulants can be complex and confusing for many providers. It involves a careful balance of a patient’s thromboembolic risk and bleeding risk. For every patient chronically taking an oral anticoagulant who will be undergoing an elective procedure, a four step approach may be considered when creating a plan for the oral anticoagulant. (1) Does the oral anticoagulant need to stop for the procedure? (2) If yes, when should the oral anticoagulant be stopped pre-procedure? (3) Does the patient require a “bridging” parenteral anticoagulant? (4) When should anticoagulation be re-started post procedure? Based on the unique features of warfarin versus the direct oral anticoagulants (DOAC), a unique, personalized plan should be developed and tailored to the individual patient. Anticoagulant specialists, such as anticoagulation clinic pharmacists, may help facilitate this process.
Keywords: Oral anticoagulant, direct oral anticoagulant (DOAC), warfarin, peri-procedural management
Background
Each year, an estimated 2 million Americans are diagnosed with either atrial fibrillation (AF) or venous thromboembolism (VTE) and require long-term anticoagulation therapy to prevent serious thromboembolic complications.1 Given an increasing prevalence with age, these patients often require other health care services for prevention or treatment of comorbid conditions. This affects approximately 250,000 patients with atrial fibrillation annually in North America.2
Common procedures for anticoagulated patients include screening endoscopy, cardiac catheterization, urologic surgery, and orthopedic surgery.3 As each of these procedures caries a significant risk of bleeding, it is generally prudent to stop anticoagulants at the time of the surgery. This allows the surgeon to proceed without a significant risk of bleeding. Once operative hemostasis has been achieved, anticoagulation is resumed with an eye towards preventing thromboembolic complications.
Traditionally, the only available oral anticoagulant in most of the world was warfarin. Because of a long effective half-life and many drug-drug interactions, a complex peri-procedural management strategy was developed which often involved the use of an overlapping (“bridging”) parenteral anticoagulant while the anticoagulant effect of warfarin wore off pre-procedurally and restarted post-procedurally. This decision-making process involves assessing a patient’s thromboembolic risk as well as the bleeding risk associated with both patient-specific factors and the procedure itself.4 Since 2009, the introduction of four direct oral anticoagulants (DOAC) has added additional complexity to this decision-making process. Unlike warfarin, the DOAC medications have a much shorter time-to-onset and half-life, negating the need for any overlapping or “bridging” anticoagulation.
A general approach to patients taking chronic oral anticoagulants who are planning to undergo a surgical procedure can be summed up with four important questions:
Does the oral anticoagulant need to stop for the procedure?
If yes, when should the oral anticoagulant be stopped pre-procedure?
Does the patient require a “bridging” parenteral anticoagulant?
When should anticoagulation be re-started post-procedure?
To answer each of these questions, clinicians must assess the patient’s thromboembolic risk, associated bleeding risks (patient- and procedure-specific), understand the oral anticoagulant’s properties, and assess the patients’ renal function (particularly for patients taking DOAC medications or using “bridging” anticoagulants).
Assessing Thromboembolic Risk
To best inform the length of time a patient can safely be without systemic anticoagulation, an understanding of thromboembolic risk is paramount. However, little contemporary data is available to guide this process and most risk stratification tools are based largely on expert opinion.
For patients with AF, the 2012 American College of Chest Physicians (ACCP) guidelines primarily used the Congestive heart failure, Hypertension, Age, Diabetes mellitus, and Stroke (CHADS2) score to classify patients into low, intermediate, and high thromboembolic risk (Table 1).4 A more recent expert consensus document from the American College of Cardiology (ACC) modified these risk elements based on the more recent and commonly used Congestive Heart Failure, Hypertension, Age, Diabetes, Stroke, Vascular Disease, and Sex Category (CHA2DS2-VASc) risk stratification scheme.2
Table 1.
Thromboembolic Risk Stratification
| Thromboembolic Risk Category | Atrial Fibrillation | Venous Thromboembolism | Mechanical Heart Valve |
|---|---|---|---|
| High (>10% annual thromboembolic risk) |
|
|
|
| Intermediate (5–10% annual thromboembolism risk) |
|
|
|
| Low (<5% annual thromboembolic risk) |
|
|
|
Modified from the 2012 American College of Chest Physicians guideline and 2017 American College of Cardiology Expert Consensus Decision Pathway.2,4 Mechanical valve thromboembolic risk factors: atrial fibrillation, congestive heart failure, hypertension, age > 75, diabetes. VTE – Venous Thromboembolism
For patients with VTE, 2012 ACCP guidelines risk stratify based on the time since VTE diagnosis and the presence of severe or non-severe thrombophilias. It should be noted that clinicians are not advised to test for thrombophilias purely for peri-procedural risk stratification. Because the more clinically significant thrombophilias are relatively rare, it is reasonable to assume no thrombophilia is present at the time of peri-procedural risk stratification unless prior test was done for another clinical purpose.
For patients with mechanical heart valves, the thromboembolic risk is assessed based on the type and location of the mechanical valve as well as any pro-thrombotic risk factors (e.g. AF, congestive heart failure, hypertension, diabetes, prior stroke, and age > 75 years).
In general, patients at high thromboembolic risk are felt to require shorter periods of time without anticoagulation therapy while patients at low thromboembolic risk can be safely managed for 1–2 weeks without full dose systemic anticoagulation for a surgical procedure. However, prospective data to support this approach is minimal and the paradigm is currently undergoing investigation (NCT00432796).5
Assessing Bleeding Risk
The bleeding risk for a patient is a combination of patient-specific clinical factors as well as procedure-specific risks of bleeding. Therefore, it is not as simple to create risk charts for bleeding as has been done for thromboembolic risk. Patient-specific elements that contribute to bleeding risk include any recent history of significant bleeding, concurrent use of specific medications (e.g. aspirin), and platelet or clotting abnormalities (Table 2). Procedure-specific elements are based on the degree of procedural invasiveness and anatomic location of the procedure.
Table 2.
Patient- and Procedure-specific Bleeding Risk Factors
| Patient-specific High Bleeding Risk Factors | High Bleeding Risk Procedures |
|---|---|
| Recent (<3 months) major bleeding event (including intracranial hemorrhage) | Urologic surgery and procedures |
| Thrombocytopenia | Pacemaker or implantable cardioverter-defibrillator device implantation |
| Concurrent anti-platelet medication use (e.g. aspirin) | Colonic polyp resection (usually >1–2cm in size) |
| Elevated INR (>1.7) | Surgery in highly vascularized organs (e.g. kidney, liver, and spleen) |
| Prior peri-procedural bleeding | Bowel resection |
| HAS-BLED Score of 3+ 1 point for each of the following:
|
Major surgery with extensive tissue injury (e.g. cancer surgery, joint arthroplasty, reconstructive plastic surgery) |
| Cardiac, intracranial, or spinal surgery |
There is little clear evidence or guidance on how the peri-procedural bleeding risk should influence decisions about peri-procedural anticoagulation use. Conceptually, patients at higher risk for bleeding may benefit from longer periods without full dose systemic or overlapping/bridging anticoagulants.
Key Questions to Determine Peri-procedural Anticoagulation Management
Does the anticoagulant need to stop for the procedure?
Many surgical procedures can be safely performed without interrupting systemic anticoagulation. This is true for most dermatologic, dental, and ophthalmologic (e.g. cataract) surgeries.4 More recent data has demonstrated that continuous anticoagulation, with either warfarin or a DOAC, may be safer than interrupted therapy for patients undergoing pacemaker or implantable cardioverter defibrillator placement and radiofrequency ablation for AF when the degree of anticoagulation is well controlled (e.g. INR < 3).6–9
If the anticoagulants need to be stopped, when should the oral agent be stopped pre-procedure?
The goal of stopping an anticoagulant pre-procedure is to ensure sufficiently low levels of anticoagulant activity at the time of the procedure as to not induce excessive bleeding or prevent hemostasis when desired. For patients taking warfarin, this can be easily measured using the INR value. For patients on low-molecular-weight heparin (LMWH) injections or a DOAC, rapidly available coagulation tests are frequently limited. Instead, clinicians can rely on the predictable pharmacologic effect based on renal function to estimate when the all drug effects are no longer likely to be present. In most patients, this means holding the medications for 1–3 days prior to a procedure.
Does the patient require a “bridging” parenteral anticoagulant?
This question only applies to patients taking warfarin (and other vitamin K antagonists) and not to patients taking DOAC medications. Because of the long effective half-life of warfarin, there are often gaps of 3–5 days when the drug is stopped before normal coagulation function has returned. During that time, for select patients, there may be benefit in providing a bridging parenteral anticoagulant with a shorter half-life. However, this practice should be limited to patients for whom forgoing systemic anticoagulation would place them at unnecessarily high thromboembolic risk.
Because DOACs have relatively short half-lives (~12 hours), there is no need to use parenteral “bridging” anticoagulants peri-procedurally.2,10 In fact, it is reasonable to think of the DOAC medicines as having similar profiles (e.g. quick onset and short half-lives) to low-molecular-weight heparin, but in an oral form.
When should the oral anticoagulant be re-started post-procedure?
This is, perhaps, the most underappreciated question in peri-procedural anticoagulation management. While much of the focus is on when to stop the anticoagulant and which patients require bridging therapy, post-operative resumption of anticoagulation is a significant (perhaps the largest) factor influencing post-operative bleeding. There is rarely a need to start full dose, rapidly active, systemic anticoagulation (e.g. heparin or DOACs) within 6–12 hours of most procedures. The BRIDGE trial demonstrated safety in waiting 24 to 72 hours post-procedure before starting full dose, rapidly active, systemic anticoagulation.3 Patients at higher risk for bleeding were recommended to wait 72 hours before LMWH bridging was re-initiated. This approach is especially important for DOAC-treated patients, because their anticoagulant effect peaks within a few hours (again, similar properties to low-molecular-weight heparin). Warfarin, on the other hand, often does not have full clinical effect for 5–10 days and therefore can be safely initiated as soon as the patient is able to take oral pills.
Peri-Procedural Warfarin Management
When addressing these four key questions of peri-procedural management of oral anticoagulants, it is important to highlight and recognize the key differences between warfarin and the DOACs.
Warfarin acts to inhibit the vitamin K-dependent clotting factors (II, VII, IX and X and anticoagulant proteins C and S). As such, warfarin’s antithrombotic effect is estimated based on the half-lives of these clotting factors, with factor II/prothrombin having the longest half-life (~96 hours) and reduction of this protein is needed to see the full antithrombotic effect.11 The estimated elimination half-life of warfarin is 36 to 42 hours.4
It is widely known that a standard interruption is 5 days for warfarin to reach baseline anticoagulant effect or normal hemostasis. The recent American College of Cardiology (ACC) 2017 consensus statement goes further to recommend specific pre-procedure warfarin holds based on individualized INRs (international normalized ratio).2 For INRs 1.5 to 1.9 (as measured 5 to 7 days prior to the procedure), the guidance recommends warfarin discontinuation 3 to 4 days prior to the procedure (if goal is baseline INR). For those with an INR 2.0 to 3.0, the standard 5-day warfarin hold prior to the procedure is recommended. In patients with INRs > 3.0, it is advised that warfarin may be discontinued at least 5 days prior to the procedure.
LMWHs are commonly used as bridging agents due to a variety of factors including fixed dosing protocols with a relatively predictable dose response, subcutaneous use that is widely available in the outpatient setting, short half-life, and generally no routine laboratory monitoring required.12 LMWH acts to bind to antithrombin and therefore inhibit factor Xa and to a lesser extent, thrombin (factor IIa). Peak effects of LMWH are seen within 3 to 5 hours (based on anti-Xa activity) and the elimination half-life is estimated at 3 to 6 hours, or longer in patients with renal insufficiency. These parenteral agents are renally eliminated and dose adjustments are recommended in patients with creatinine clearance (CrCl) less than 30mL/min or UFH may be preferred. While routine measurement of anti-Xa levels is generally not recommended, levels may be considered in certain patient populations including those who are on long-term therapy, patients with renal insufficiency (CrCl < 30mL/min), obese patients, and pregnant patients.
Treatment doses of LMWHs are recommended when using as a bridging agent.4 In determining dose of LMWH when used as a bridging agent, the patient’s indication for anticoagulation, previous history with LMWH or heparin should be considered (to rule out allergy or history of heparin-induced thrombocytopenia), the patient’s actual weight (in kilograms), and renal function (CrCl as calculated via Cockcroft-Gault equation). Dosing frequency is every 12 or 24 hours based on indication, product, and renal function. Enoxaparin is dosed 1.5mg/kg Q 24 hours or 1mg/kg Q 12 hours.
Several studies suggest that bridging is not necessary for many patient groups for whom warfarin is being interrupted. One such group are patients with atrial fibrillation undergoing device implantation or ablation procedures. In a multicenter, randomized controlled, single-blind study, patients who required a pacemaker or implantable cardioverter-defibrillator surgery and were on warfarin with at least a moderate risk of thromboembolism (≥ 5% annual risk), were assigned to continuing warfarin (with median INR of 2.3) or bridging with either LMWH or heparin (89% of patients in this arm received LMWH).6 The primary outcome of clinically significant device pocket hematoma occurred more frequently in the bridging group than in the group that continued warfarin (16.0% vs. 3.5%, RR 0.19, 95% CI 0.10–0.36, p<0.001). Additionally, patients reported greater satisfaction in the perioperative anticoagulation management in the group that continued warfarin. Another large, prospective, randomized, open-label multicenter study compared warfarin continuation versus warfarin discontinuation in terms of thromboembolic and bleeding risk during radiofrequency catheter ablation.7 Patients who discontinued warfarin were bridged with therapeutic doses of LMWH until the evening before the ablation and IV heparin on the day of the procedure. Thromboembolic events within 48 hours of the procedure occurred more frequently in the group that discontinued warfarin compared to the group that continued (4.9% vs. 0.25%, RR 0.051, 95% CI 0.012–0.211, p<0.001). The authors report that one of the strongest predictors of thromboembolic events was warfarin discontinuation/bridging. Major bleeding rates were not statistically different, however minor bleeding rates were higher in the group that discontinued warfarin and bridged.
The Bridging Anticoagulation in Patients who Require Temporary Interruption of Warfarin Therapy for an Elective Invasive Procedure or Surgery trial (BRIDGE study) was a landmark study that explored the safety and efficacy of bridging LMWH use for patients on chronic warfarin therapy for stroke prevention in non-valvular atrial fibrillation. Previous observational trials have argued that bridging patients increases the peri-procedural bleed risk without the benefit of greater thromboembolic protection.13 The BRIDGE trial was a randomized, double-blind, placebo-controlled, large-scale, multi-site trial. The study demonstrated that forgoing bridging was noninferior to use of LMWH bridging for preventing arterial thromboembolism (0.4% in the no-bridging group and 0.3% in the bridging group, p=0.01 for non-inferiority). Avoiding the use of LMWH bridging also resulted in less major bleeding than administration of LMWH bridging therapy. Both the thromboembolic and bleeding outcomes occurred less frequently than expected in the overall trial population. It should be noted, the patient population included in the study had a mean CHA2DS2-VASc score of 2.3 and did not include patients with mechanical heart valves, recent thrombotic event within the previous 12 weeks, or patients undergoing cardiac, intracranial or intraspinal surgery.
In the BRIDGE trial, the standardized protocol for management during the perioperative period involved stopping warfarin 5 days prior to the procedure and starting the study medication (LMWH or placebo) 3 days prior to the procedure with the last dose given 24 hours prior to the procedure (Table 3). Post procedure, warfarin (at previous therapeutic dose) was resumed within 24 hours and study medication was resumed as based on bleeding risk of the procedure (either within 12–24 hours for low bleed risk or within 48–72 hours for high bleed risk). The study medication was then continued until the INR was >= 2.0.
Table 3.
BRIDGE trial anticoagulation protocol3
| Day (around procedure) | Protocol |
|---|---|
| −5 | Stop warfarin |
| −3 | Start bridging agent (LMWH or placebo) |
| −1 | Stop bridging agent 24 hours prior to procedure |
| 0 (procedure day) | |
| 1 | Resume warfarin within 24 hours. Resume bridging agent within 12 to 24 hours for low bleed risk |
| 2–3 | Resume bridging agent within 48 to 72 hours for high bleed risk procedures |
| 5–10 | Stop bridging agent when INR reaches 2.0 or greater |
LMWH – low-molecular-weight heparin.
PERIOP-2 is an ongoing multicenter, randomized, placebo controlled trial that may address safety and efficacy of LMWH in the post-operative period in patients on warfarin who have mechanical heart valves or higher risk atrial fibrillation/flutter patients (NCT00432796). This trial may provide novel, high-level trial insight into the timing of resuming LMWH post-operatively.
Post procedure, consideration of resuming warfarin should be individualized and subject to proceduralist approval, as hemostasis and possible bleeding complications should be addressed. Generally, it is recommended to resume warfarin (at previous pre-procedure dose) within 12 to 24 hours of the procedure as it takes days to resume the full therapeutic effect. If LMWH had been used as a bridging agent pre-procedure (as determined that the patient had moderate to high thrombotic risk), LMWH would be resumed post procedure at full dose with surgeon/proceduralist approval. The procedure bleed risk may need to be addressed when determining when to resume the parenteral agent. For a low bleed risk procedure, it may be appropriate to restart the LMWH within 24 hours of the procedure (possibly the evening of the procedure) and with high bleed risk procedures, it may be appropriate to resume 48 to 72 hours post procedure.3
Peri-Procedural DOAC Management
The DOACS are becoming more popular and widely used, therefore, peri-procedural consideration must be taken regarding their unique properties that differentiate themselves from warfarin.
Dabigatran is an oral direct thrombin/factor IIa inhibitor. The other three DOACs (rivaroxaban, apixaban, and edoxaban) are oral selective factor Xa inhibitors. Indications for use somewhat vary with all being approved for reducing the risk of stroke and systemic thromboembolism in patients with nonvalvular atrial fibrillation and treatment of deep vein thrombosis and pulmonary embolism. Because all of the DOACs (to varying degrees) are renally eliminated, dosing is based on the level of renal function. Of note, the DOACs are not well studied in patients with CrCL< 30mL/min and often have FDA warnings for those patients.
When it is necessary to consider a peri-procedural interruption of a DOAC, pharmacokinetic properties of these medications must be considered. Unlike warfarin, the DOACs have a short time to peak effect, relatively short half-lives, and are subject to renal elimination (see Table 4). Half-lives are similar across the DOACs (~10–12 hours). The extent of renal clearance is variable based on the individual DOAC, and it is important to calculate the patient’s creatinine clearance (utilizing actual body weight with the Cockcroft-Gault equation, as was used in the major clinical trials) when developing a peri-procedural plan.14 In general, the DOACs may act more similarly to the parenteral LMWHs given these properties. Bridging is rarely (if ever) recommended when interrupting the DOACS.10,15
Table 4.
Pharmacokinetic considerations when using the DOACs peri-procedurally
Currently available perioperative DOAC data is primarily generated from major randomized trial substudies. In the perioperative substudy of the RE-LY trial, bridging was used in 15.4% of dabigatran patients (and about 40% of patients in North America and Europe) and more than a quarter (27.5%) of warfarin patients.15 In both dabigatran and warfarin bridging groups, major bleeding occurred more often in patients who were bridged. The risk of stroke or VTE was not significantly different between bridging and non-bridging groups for either dabigatran- or warfarin-treated patients (0.5 % vs 0.3 % [p=0.46] and 0.5% vs 0.2% [p=0.321], respectively). This study’s authors recommended that patients treated with dabigatran forego any bridging therapy peri-procedurally.
In the non-randomized, non-controlled substudy of ARISTOTLE, there were no differences seen in stroke/systemic embolism (0.57% vs. 0.35%, OR 0.601, 95% CI 0.322–1.120) or major bleeding rates (1.93% vs. 1.62%, OR 0.846, 95% CI 0.614–1.166) between the warfarin- and apixaban-treated patients.16 The majority of the procedures in the study were classified as “non-major” and the most common procedures were dental extraction/oral surgery (14.6%) and colonoscopy (9.9%). Therefore, anticoagulation was not stopped during the peri-procedural time in more than a third (37.5%) of the procedures.
Consideration may be given to the type and bleed risk of the procedure and if DOAC interruption is necessary. In the ROCKET AF retrospective analysis of non-valvular AF (NVAF) patients who temporarily interrupted either rivaroxaban or warfarin, 40% of the more than 4500 study participants interrupted for a surgical procedure.17 The low rates of systemic embolism or stroke (0.30% and 0.41%) and major bleeding (0.99% and 0.79%) were similar during the 30-day post procedure period between rivaroxaban and warfarin. Similar to the apixaban ARISTOTLE substudy, the most common procedures were either dental procedures (17%) or colonoscopy/GI endoscopy (17%). Of note, bridging was only used in 6% of all temporary interruptions.
Additional DOAC Trial Data
Dabigatran
Current prescribing peri-procedural recommendation is to discontinue dabigatran 1–2 days prior to surgical procedures (if CrCL>50mL/min) or 3–5 days prior if CrCL < 50mL/min and longer times may be considered for major surgery. A prospective non-randomized cohort study analyzed a protocol for dabigatran interruption for surgical procedures.18 The protocol considered the patient’s renal function (using CrCl), estimated half-life of dabigatran, and procedure bleeding risk to determine the timing of the last dose of dabigatran pre-procedure. More than 500 patients at multiple sites were analyzed, with 60% of procedures classified as standard bleeding risk and 40% high bleed risk. Post procedure, about 40% of patients were started on a 75mg reduced dose of dabigatran on the day of the procedure. Bridging was used in 9 patients postoperatively and avoided pre-operatively. Ten patients had a major bleeding event.
A randomized, blinded end-point assessments, open-label, multicenter trial compared uninterrupted warfarin (INR goal 2.0 to 3.0) to uninterrupted dabigatran (150mg twice daily) in paroxysmal or persistent nonvalvular atrial fibrillation patients undergoing catheter ablation.9 Of the 635 patients who underwent the ablation, significantly more patients had a major bleeding event within the 8 week post ablation study period in the warfarin group than in the dabigatran group (27 patients total; 6.9% in the warfarin group vs. 1.6% in the dabigatran group, HR 0.22, 95% CI 0.08–0.59). Only one thromboembolic event (TIA) occurred (warfarin group). The trial’s small sample size did not allow for noninferiority statements to be made.
Rivaroxaban/Apixaban/Edoxaban
Based on package insert recommendations, rivaroxaban and edoxaban should be discontinued at least 24 hours prior to a surgery or procedure and resumed when there is established, adequate hemostasis. Similarly, apixaban prescribing information recommends discontinuation of apixaban at least 24 hours prior to low bleed risk procedure and at least 48 hours prior to moderate or high bleed risk procedure. Resumption of apixaban is recommended post adequate hemostasis. See Table 5 for recommendations on timing of the last dose of the DOAC prior to the procedure based on the procedure bleed risk and the patient’s renal function.
Table 5.
Last dose of the DOAC prior to elective procedure*
| Low bleed risk procedure | High (unknown, moderate) bleed risk procedure | |
|---|---|---|
| Rivaroxaban, apixaban, edoxaban | ||
| CrCl ≥ 30 mL/min | ≥ 24 hours | ≥48 hours |
| CrCl 15–29 mL/min | ≥ 36 hours | Data lacking. May consider specific anti-Xa level or holding ≥ 72 hours |
| CrCl < 15 mL/min | Data lacking. May consider specific anti-Xa level or holding ≥ 48 hours | |
| Dabigatran | ||
| CrCl ≥ 80 mL/min | ≥ 24 hours | ≥ 48 hours |
| CrCl 50–80 mL/min | ≥ 36 hours | ≥ 72 hours |
| CrCl 30–49 mL/min | ≥ 48 hours | ≥ 96 hours |
| CrCl 15–29 mL/min | ≥ 72 hours | ≥ 120 hours |
| CrCl < 15mL/min | Not indicated. May consider measuring dilute Thrombin Time | |
The COMPARE trial is a prospective, randomly assigned descriptive trial comparing uninterrupted rivaroxaban and vitamin K antagonists in approximately 250 patients with NVAF who are undergoing catheter ablation.8 In this trial, major bleeding events and major thromboembolic events were rare. Interestingly, all 3 events (1 major bleed and 2 thromboembolic events) occurred in patients on vitamin K antagonists, not in patients taking rivaroxaban. Use of uninterrupted DOACs may be an option in patients undergoing catheter ablation.
Similar to the BRUISECONTROL trial with patients on warfarin, a DOAC trial that is currently ongoing, intends to examine continuing the DOACs (dabigatran, rivaroxaban, apixaban) compared to DOAC interruption (a full day prior to surgery and resuming at least 24 hours post procedure) in patients undergoing pacemaker or defibrillator surgery (NCT01675076).6 Clinically significant hematoma and perioperative bleeding and thrombotic events are intended to be examined within a 2 week postoperative timeframe.
Routine laboratory monitoring of the DOACs is not recommended prior to surgical procedures. In rare circumstances when clinicians seek to determine a drug level, specific laboratory tests may be somewhat useful (if they are available). For example, dTT (dilute thrombin time) may be useful in quantitatively measuring dabigatran (trough level), however it may not be a widely available test.19 Anti-Xa assays (trough levels) may provide quantitative measurements of rivaroxaban, apixaban and edoxaban, however they must be specific to the individual drug (example: specific apixaban anti -Xa level). The ongoing PAUSE trial (NCT02228798) will assess the effect of holding DOAC medications on coagulation laboratory measurements prior to procedure in patients with AF.
Post procedure, resumption of the DOACs should be individualized with consideration by and approval of the proceduralist. Unlike with warfarin, the DOACs reach peak therapeutic effects within hours, therefore it may be more crucial for hemostasis to be achieved. Procedure bleed risk and patient renal function must be considered. For low bleed risk procedures, resuming full dose DOAC the following day (ACC guidance) may be advised. Waiting 48 to 72 hours post procedure may be considered after high bleed risk procedures.2
The trials involving patients started on dabigatran post hip replacement surgery and rivaroxaban or apixaban post hip or knee replacement surgery to prevent deep venous thrombosis/pulmonary embolism provide some post procedure guidance in this patient population. Following hip or knee orthopedic surgery, it is recommended for apixaban 2.5mg twice daily to be initiated 12 to 24 hours post procedure and rivaroxaban 10mg once daily to be initiated (6–8 hours after procedure).20–22 Following hip replacement surgery, lower dose dabigatran is recommended (1–4 hours post procedure if hemostasis has been achieved), followed by 220mg once daily thereafter in patients with CrCL> 30mL/min.23
Overall, there is a lack of studies for when and at what dose to resume the DOACs post procedure in patients with AF or VTE indications.
Given the current lack of randomized, placebo controlled trials regarding peri-procedural management of the DOACs, it is not surprising that there is confusion and variability in management of these medications. Bridging of the DOACs for short-term peri-procedural interruptions is not recommended, however providers continue to do so.24,25
Role of Anticoagulation Clinics
A clinical pharmacist or nurse in an anticoagulation service may serve as a clinical collaborator and initiate the discussion between primary anticoagulation prescriber, proceduralist, and patient to best ensure the ideal peri-procedural plan. Given the multiple step process of anticoagulation peri-procedural management, it is clear the development of an ideal plan may be complex and time consuming. The peri-procedural plan often requires patient education, especially when the patient is bridging during a warfarin interruption. Education often is necessary for patients, especially for those previously on warfarin who now need to learn a new management strategy for DOAC medications.
Given the complexities of these high-risk medications, clinical pharmacists with anticoagulation expertise are often already embedded in institutions’ anticoagulation services. The anticoagulation-service clinical pharmacist may wear many hats and have a variety of functions. At a provider level, the clinical pharmacist may facilitate collaboration and communication between multiple disciplines/providers and potentially across multiple institutions. Providers unfamiliar with recent anticoagulation clinical evidence may benefit from anticoagulation pharmacist specialist recommendation. Pharmacists often are involved in developing institution specific clinical practice guideline committees and can share this information with providers who are unaware.
At the patient level, pharmacists can provide patient specific education and communicate the plan that was developed in collaboration with the patient’s primary anticoagulation provider and proceduralist. Pharmacists may be involved in cost considerations of the potentially expensive LMWHs or DOACs.
Conclusion
For every patient chronically taking an oral anticoagulant who is undergoing an elective procedure, a four-step approach may be considered when creating a plan for the anticoagulant. (1) Does the oral anticoagulant need to stop for the procedure? (2) If yes, when should the oral anticoagulant be stopped pre-procedure? (3) Does the patient require a “bridging” parenteral anticoagulant? (4) When should the oral anticoagulant be re-started post-procedure? Warfarin and the DOACs have significant differences in time to peak effects, half-lives, extent of renal elimination, as well as other differences and a plan must be carefully developed for each individual patient. Peri-procedural management of oral anticoagulants is not well studied and more high level trials are needed to determine optimum management of these agents. An anticoagulation specialist may be helpful in facilitating the process of creating a peri -procedural plan.
Abbreviations
- ACC
American College of Cardiology
- ACCP
American College of Chest Physicians
- AF
Atrial fibrillation
- CHADS2
congestive heart failure, hypertension, age > 75, diabetes, and stroke
- CHA2DS2-VASc
congestive heart failure, hypertension, age, diabetes, stroke, vascular disease, and sex category
- CrCl
creatinine clearance
- DOAC
oral anticoagulant
- HAS-BLED
hypertension, abnormal renal or liver function, stroke history, prior major bleeding or predisposition to bleeding, labile INR, elderly, concurrent drug or alcohol use
- LMWH
low-molecular-weight heparin
- NVAF
Non-valvular atrial fibrillation
- VTE
venous thromboembolism
Footnotes
EM has no disclosures
Author Disclosures:
GDB received grant support from the National Heart, Lung, and Blood Institute, Pfizer/BMS, and Blue Cross-Blue Shield of Michigan. He has served as a consultant for Pfizer/BMS, Janssen and Portola.
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References
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